The ability of exogenously administered nucleotide molecules to mediate gene silencing was discovered nearly 30 years ago. Ever since, this technology has been utilized as a research tool to study gene function, and over time it has been developed for treatment of diseases arising from the abnormal over-expression or over-activity of a particular gene, such as cancer, autoimmune and cardiovascular diseases, wound healing and viral infections. This technology, referred to herein as antisense therapeutics, includes a range of technologies differentiated by the approaches they use to break down the mRNA. Approaches currently generating interest include, for example, RNA interference (RNAi), micro-RNA, and the use of conventional antisense deoxynucleotide technologies.
Further progress in this field requires improvement in the systemic and cellular delivery of these antisense therapeutics to their targets. Some of the barriers at the systemic level include survival against unfavorable interactions with serum proteins present in the bloodstream, avoidance of accumulation in non-target organs such as lung, liver and kidney, and targeting of the diseased or infected cells. Once the antisense therapeutics have overcome these barriers, they must maneuver their way into the target cell and finally to the target mRNA within the cell. Some of the challenges to antisense therapeutics delivery at the cellular level include efficient entry into the cell, escape from degradative lysosomes, and release into the cytoplasm.
While viral vectors are also being used for delivery of such antisense therapeutics and gene delivery, safety concerns persist. Although iterative design of non-viral vectors has endowed them with attributes for overcoming some of the systemic and cellular barriers in the delivery of antisense therapeutics, their delivery efficiencies are generally too low and their cytotoxicities are generally too high. A major barrier to the intracellular delivery of antisense therapeutics is their sequestration in endosomes, which eventually fuse with lysosomes, leading to degradation of their contents.
Accordingly, there is a need in the art for methods and materials that improve intracellular delivery of antisense therapeutics.